This purpose of this study to identify brain mechanisms mediating the symptoms of bipolar disorder (BD)in children and adolescents. To do this, patients and controls complete standardized behavioral paradigms designed to assess responses to emotional stimuli, such as reward and punishment, or faces displaying emotion. Approximately 100 patients and matched controls have been assessed on a battery of such paradigms. Taken together, these data indicate that children with BPD have difficulty adapting their behavior in response to changes in emotional stimuli in their environment. These deficits are evident on response reversal tasks, two tasks testing their ability to inhibit a dominant motor response and initiate another, and a task that assesses their behavior in the context of frustration. In addition, our data indicate that children with BPD have difficulty identifying facial emotion accurately. Using functional MRI, we have identified amygdala hyperactivity that is associated with the face labeling deficit, and prefrontal and striatal abnormalities associated with deficits in motor inhibition and response flexibility. Based on these findings, we are initiating genetic studies aimed at identifying associations between polymorphisms associated with bipolar disorder and abnormal patterns of brain activation identified with functional MRI. In addition, we have begun a study of children who are at risk for BPD because they have a parent or sibling with the illness. The goal of this study is to ascertain whether the behavioral deficits that we identified are familial and therefore may be candidate endophenotypes for BPD. Thus far, our data indicate that youth at risk for BD show deficits in face emotion identification similar to those seen in youth with BD, indicating that such deficits may be related to causes of the illness, rather than simply being a result of the child being ill. In addition, this year we recruited children with ADHD as a psychiatric comparison group for children with BPD, and are currently analyzing functional MRI data to ascertin how brain function may differ among these groups while performing face emotion identification and response flexibility tasks. Finally, we continue to assess the psychiatric status of family members, bank genetic samples from patients and parents for use in future studies, and follow the patients longitudinally (clinically and with structural MRI scans).